biostudies-literatureRothemann RADeutsche ForschungsgemeinschaftMinisterium für Kultur und Wissenschaft NRW5506-5522https://www.ebi.ac.uk/biostudies/studies/S-EPMC11653687biostudies-literatureUnknown291(24)The mitochondrial disulphide relay machinery is essential for the import and oxidative folding of many proteins in the mitochondrial intermembrane space. Its core component, the import receptor MIA40 (also CHCHD4), serves as an oxidoreductase but also as a chaperone holdase, which initially interacts with its substrates non-covalently before introducing disulphide bonds for folding and retaining proteins in the intermembrane space. Interactome studies have identified diverse substrates of MIA40, among them the intrinsically disordered HCLS1-associated protein X-1 (HAX1). Interestingly, this protein does not contain cysteines, raising the question of how and to what end HAX1 can interact with MIA40. Here, we demonstrate that MIA40 non-covalently interacts with HAX1 independent of its redox-The FEBS journalInteraction with the cysteine-free protein HAX1 expands the substrate specificity and function of MIA40 beyond protein oxidation.PMC11653687411422114251546152269925409435235019Habich MGerlich SRiemer JMurschall LMPeker EHoehne-Wiechmann MNKnaup LKStobbe DRacho JLapacz KJUlrich KRothemann RAfalseInteraction with the cysteine-free protein HAX1 expands the substrate specificity and function of MIA40 beyond protein oxidation.The mitochondrial disulphide relay machinery is essential for the import and oxidative folding of many proteins in the mitochondrial intermembrane space. Its core component, the import receptor MIA40 (also CHCHD4), serves as an oxidoreductase but also as a chaperone holdase, which initially interacts with its substrates non-covalently before introducing disulphide bonds for folding and retaining proteins in the intermembrane space. Interactome studies have identified diverse substrates of MIA40, among them the intrinsically disordered HCLS1-associated protein X-1 (HAX1). Interestingly, this protein does not contain cysteines, raising the question of how and to what end HAX1 can interact with MIA40. Here, we demonstrate that MIA40 non-covalently interacts with HAX1 independent of its redox-2024-01-01T00:00:00Z2024 Dec2025-04-26T17:10:31.087Z2025-04-06T15:25:09.565ZS-EPMC116536873956480610.1111/febs.17328